On September 12, 2022 Alpine Immune Sciences, Inc. (NASDAQ: ALPN), a leading clinical-stage immunotherapy company focused on developing innovative treatments for cancer and autoimmune and inflammatory diseases, reported clinical updates from two wholly owned programs, ALPN-303 and davoceticept (Press release, Alpine Immune Sciences, SEP 12, 2022, View Source [SID1234619404]). A broad development plan for ALPN-303 will be presented, including a proof-of-concept phase 2 study in systemic lupus erythematosus (SLE) and basket studies in renal, hematologic, and dermatologic autoimmune diseases, with initial clinical data from the baskets expected in the second half of 2023.
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"We are pleased to share these important updates which we believe strongly support and frame the next phase of development for these two programs," said Stanford Peng, MD, PhD, Alpine’s President and Head of R&D. "The initial healthy volunteer data with ALPN-303 suggest a differentiated and potentially best-in-class development profile, which we anticipate could have a meaningful impact on clinical outcomes in SLE and also potentially a wide range of autoantibody-related inflammatory diseases. Davoceticept, our lead Immuno-oncology program, continues to show encouraging signs of meaningful clinical activity with an acceptable safety profile. Renal cell carcinoma has emerged as a particular area of interest given the preliminary experience in both ongoing studies which correlates with existing translational data in the literature, supporting the importance of CD28 costimulation in this particular tumor type."
Mitchell H. Gold, MD, Alpine’s Executive Chairman and Chief Executive Officer, added, "Since our founding, we’ve made tremendous progress in advancing our platform and clinical pipeline. With these new data, we have set a clear path for the company with the goal of achieving proof-of-concept for all three development programs and of advancing each to pivotal and/or registrational studies, which will be transformational for the company."
In addition to Alpine management reviewing these data and planned clinical development plans, the R&D Day will also feature presentations by two leading experts, Vibeke Strand, MD, Biopharmaceutical Consultant and Adjunct Clinical Professor, Division of Immunology/Rheumatology, Stanford University School of Medicine, and Katy E. Beckermann, MD, PhD, Assistant Professor of Medicine, Division of Hematology/Oncology, Vanderbilt University Medical Center, who will review the current treatment landscape as well as the potential role for new treatment options in lupus and renal cell carcinoma (RCC), respectively.
R&D Day Program Highlights
ALPN-303
Well tolerated in healthy adults when administered intravenously or subcutaneously (SQ) at doses up to 960 mg.
Encouraging preliminary pharmacodynamic analyses, including reductions in circulating immunoglobulins and antibody-secreting cells (CD38hi plasmablasts/plasma cells) – the latter not previously reported with inhibitors of BAFF and/or APRIL in healthy adults, to the best of the Company’s knowledge.
Pharmacodynamic analyses further support the feasibility of convenient subcutaneous therapeutic dosing every four weeks, suggesting potential for more robust activity and greater convenience over related inhibitors of BAFF and/or APRIL.
– Doses selected for the next studies include 80 mg and 240 mg SQ every four weeks
The Company believes these encouraging data support a broad development plan including:
– A randomized, placebo-controlled phase 2 proof-of-concept study in SLE; and
– Open-label basket studies in renal, hematologic, and dermatologic autoimmune diseases with initial data anticipated in the second half of 2023.
"ALPN-303 is particularly exciting because it may be the first truly dual inhibitor of both BAFF and APRIL – a clinically validated target space for complex diseases like lupus," said Dr. Vibeke Strand. "This early human data suggest that ALPN-303 is in fact more potent and should be able to be more conveniently administered than existing candidates like the wild-type TACIs, which have already shown proof-of-concept in these diseases. Together with ALPN-303’s excellent initial tolerability, these findings strongly encourage further clinical development, and I look forward to continuing to work with this team and seeing the results of the planned studies."
Davoceticept (ALPN-202)
Engineered to provide PD-L1-dependent CD28 costimulation along with dual PD-L1/CTLA-4 checkpoint inhibition
Preliminary analyses of the ongoing dose escalation in NEON-2, the study of davoceticept in combination with pembrolizumab, show encouraging outcomes. These include evidence of tumor reduction in two subjects: a 37.8% reduction in prostate-specific antigen (PSA; 622.9 to 387.7 ng/mL) in a subject with castrate-resistant prostate cancer, and a 25.5% tumor volume reduction in a subject with poorly differentiated renal cell carcinoma (RCC) with prior primary resistance to pembrolizumab and axitinib. A third subject, with clear cell RCC including with prior primary resistance to nivolumab, achieved a durable confirmed partial response (-30%).
Across both the NEON-1 davoceticept monotherapy and NEON-2 studies, 2/5 (40%) and 3/5 (60%) of subjects have achieved a confirmed partial response or stable disease, respectively.
Dose escalation in NEON-2 is ongoing. In NEON-1, expansion cohorts in RCC, melanoma, and PD-L1-positive tumors are also ongoing.
"These initial data are compelling given the responses observed in PD-1 refractory RCC," remarked Dr. Beckermann. "Such findings are highly consistent with our own translational data demonstrating that the CD28 pathway may be relevant to the biology of treatment resistance — and strongly support further development of davoceticept, particularly in RCC."
Alpine R&D Day Conference Call and Webcast Information
A live webcast of the event will be available in the investor relations section of the company’s website at View Source A replay will be available on the Company’s website for 90 days following the live event.
About ALPN-303 and the Phase 1 (RUBY-1) Study
ALPN-303 is a dual B cell cytokine antagonist being developed for multiple autoimmune and/or inflammatory diseases. Based upon an engineered TACI (transmembrane activator and CAML interactor) domain, ALPN-303 in preclinical studies shows robust inhibition of B cell activating factor/B lymphocyte stimulator (BAFF, BLyS) and a proliferation inducing ligand (APRIL). These two pleiotropic B cell cytokines play key roles in B cell development, differentiation, and survival, and together contribute to the pathogenesis of multiple autoimmune diseases like systemic lupus erythematosus (SLE) and many other autoantibody-related inflammatory diseases. By simultaneously blocking these two cytokines, ALPN-303 has the potential to improve outcomes in patients suffering from severe autoimmune and/or inflammatory diseases. Alpine plans to conduct a phase 2 proof-of-concept study in SLE and open-label basket studies in renal, hematologic, and dermatologic autoimmune diseases, with the first of these anticipated to begin in the first half of 2023.
RUBY-1 (NCT05034484) is a phase 1, randomized, placebo-controlled study in healthy adult volunteers that has been designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of intravenously and subcutaneously administered ALPN-303.
About Davoceticept and the NEON Studies
Davoceticept (ALPN-202) is a first-in-class, conditional CD28 costimulator and dual checkpoint inhibitor intended for the treatment of cancer. Preclinical studies of davoceticept have successfully demonstrated superior efficacy in tumor models compared to checkpoint inhibition alone. NEON-1 (NCT04186637), a phase 1 monotherapy dose escalation and expansion study in patients with advanced malignancies, has completed dose escalation and is currently enrolling its expansion cohorts. NEON-2 (NCT04920383), a combination study of davoceticept (ALPN-202) and pembrolizumab, was initiated in June 2021.